This application is submitted in response to PAR-08-232. Parkinson's disease (PD) is an incurable progressive neurodegenerative disorder characterized by motor dysfunctions associated with the loss of dopaminergic neurons in the substantia nigra pars compacta. Although, symptoms can be successfully controlled in the initial stages of the disease, effective long term therapies targeting PD pathology are still lacking. Pathologically, sporadic and familial PD cases are also characterized by the presence of brain inclusions known as Lewy bodies and Lewy neurites that are primarily composed of fibrillar 1-synuclein (1- syn). The central role of 1-syn in PD pathogenesis is further supported by the finding of point mutations and genetic multiplications in the 1-syn gene in a subset of autosomal-dominant PD cases. These genetic mutations and multiplications lead to an increase in aggregated 1-syn species, which are believed to be implicated in neuronal toxicity. Therefore, strategies to increase the clearance of monomeric 1-syn (to prevent aggregation) and/or of aggregated 1-syn species (to stop or reverse aggregation) should prevent or reduce PD pathology. Our published data show that, in lysosomes, 1-syn is primarily degraded by cathepsin D (Cat. D), and that 1-syn levels can be manipulated by changes in Cat. D activity. In this application, we will test the potential of Cat. D to prevent or reduce 1-syn pathology in animal models of PD. We will use two well characterized mouse models expressing WT and A53T mutant human 1-syn, that in addition to brain inclusions, show locomotor deficits. Cat. D will be delivered to the brains of newborn and adult animals, using recombinant adeno-associated virus (rAAV) technology, and the pathology and disease progression will be measured by biochemical and immunohistochemical methods. Our studies will provide information on the feasibility of Cat. D as a therapeutic tool for PD. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is the most common movement disorder affecting more than 500,000 people in the US, and about 50,000 new cases of the disease are diagnosed every year. PD is incurable and current treatments are for most part focused on the disease symptoms. In this application, we propose to investigate new preventive and therapeutic strategies for the disease by targeting 1-synuclein, a protein involved in PD pathology.